Evaluation of the effects of metformin administration on morphine tolerance in mice

Shirooie, Samira; Esmaeili, Jamileh; Sureda, Antoni; Esmaeili, Nafiseh; Saffari, Partow Mirzaee; Yousefi‐Manesh, Hasan; Dehpour, Ahmad Reza

doi:10.1016/j.neulet.2019.134638

Cited by 6 publications

(6 citation statements)

References 25 publications

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“…Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were used to reduce the dimensionality of the data, and several principal components are used to describe the biggest difference between groups or samples. We took the two principal components t [ 1 ] and t [ 2 ] with the greatest difference as the two-dimensional diagram, t [ 1 ] as the abscissa and t [ 2 ] as the ordinate, while t [ 1 ] and t [ 2 ] of each sample point are different, such that they were scattered in the diagram and finally formed a scatter diagram. In this way, the PCA loading plot was obtained to observe the clustering, dispersion, and outliers of the sample, and the PLS-DA loading plot observed the difference between the groups.…”

Section: Methodsmentioning

confidence: 99%

“…Morphine is a prescription opiate, most commonly used for pain management, and can provide significant relief to patients suffering from pain [ 1 ]. However, prolonged use of morphine can lead to a situation of analgesic tolerance and dependence [ 2 ]. In contrast, heroin, or diacetylmorphine, is an opiate drug with two acetyl groups added to the basic structure of morphine [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

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Identification of Morphine and Heroin-Treatment in Mice Using Metabonomics

Zhang

Wei

et al. 2021

Metabolites

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Although heroin and morphine are structural analogues and morphine is a metabolite of heroin, it is not known how the effect of each substance on metabolites in vivo differs. Heroin and morphine were administered to C57BL/6J mice in increasing doses from 2 to 25 and 3 to 9 mg kg−1 (twice a day, i.p.), respectively, for 20 days. The animals underwent withdrawal for 5 days and were readministered the drugs after 10 days. Serum and urine analytes were profiled using gas chromatography-mass spectrometry (GC-MS), and metabolic patterns were evaluated based on metabonomics data. Metabonomics data showed that heroin administration changed metabolic pattern, and heroin withdrawal did not quickly restore it to baseline levels. A relapse of heroin exposure changed metabolic pattern again. In contrast, although the administration of morphine changed metabolic pattern, whether from morphine withdrawal or relapse, metabolic pattern was similar to control levels. The analysis of metabolites showed that both heroin and morphine interfered with lipid metabolism, the tricarboxylic acid (TCA) cycle and amino acid metabolism. In addition, both heroin and morphine increased the levels of 3-hydroxybutyric acid and citric acid but decreased the serum levels of 2-ketoglutaric acid and tryptophan. Moreover, heroin and morphine reduced the levels of aconitic acid, cysteine, glycine, and oxalic acid in urine. The results show 3-Hydroxybutyric acid, tryptophan, citric acid and 2-ketoglutaric acid can be used as potential markers of opiate abuse in serum, while oxalic acid, aconitic acid, cysteine, and glycine can be used as potential markers in urine.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of Morphine and Heroin-Treatment in Mice Using Metabonomics

Zhang

Wei

et al. 2021

Metabolites

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“…The results are based on the fact that chronic and acute administration of metformin significantly decreased the level of nitric oxide. Moreover, by activating the AMPK pathway, metformin inhibits the activity of mTOR (mammalian target of rapamycin) whose increase contributes to the emergence of opioid tolerance [ 63 ]. Furthermore, a study showed that metformin can reduce mechanical allodynia by down-regulating NF-κB (nuclear factor kappa B) expression [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

The Influence of Sildenafil–Metformin Combination on Hyperalgesia and Biochemical Markers in Diabetic Neuropathy in Mice

Pușcașu,

Ungurianu,

Șeremet

et al. 2023

Medicina

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Background and objectives: Worldwide, approximately 500 million people suffer from diabetes and at least 50% of these people develop neuropathy. Currently, therapeutic strategies for reducing diabetic neuropathy (DN)-associated pain are limited and have several side effects. The purpose of the study was to evaluate the antihyperalgesic action of different sildenafil (phosphodiesterase-5 inhibitor) and metformin (antihyperglycemic agent) combinations in alloxan-induced DN. Methods: The study included 100 diabetic mice and 20 non-diabetic mice that were subjected to hot and cold stimulus tests. Furthermore, we determined the influence of this combination on TNF-α, IL-6 and nitrites levels in brain and liver tissues. Results: In both the hot-plate and tail withdrawal test, all sildenafil–metformin combinations administered in our study showed a significant increase in pain reaction latencies when compared to the diabetic control group. Furthermore, all combinations decreased blood glucose levels due to the hypoglycemic effect of metformin. Additionally, changes in nitrite levels and pro-inflammatory cytokines (TNF-α and IL-6) were observed after 14 days of treatment with different sildenafil–metformin combinations. Conclusions: The combination of these two substances increased the pain reaction latency of diabetic animals in a dose-dependent manner. Moreover, all sildenafil–metformin combinations significantly reduced the concentration of nitrites in the brain and liver, which are final products formed under the action of iNOS.

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“…Additionally, the complexity of chronic pain syndromes requires tailored pharmacological interventions and innovative drugs to effectively and safety control pain. Some studies have reported how different experimental drugs can be administered in combination (if they prove to be safe) with clinical opioids (e.g., intrathecal ziconotide, an N-type calcium ion channel inhibitor, ω-conotoxins with intrathecal morphine [35] or metformin, a potent antidiabetic drug [36]) to provide better pain relief and fewer adverse events than opioids alone. Moreover, the management of ongoing pain has been improved by the use of long-acting opioid agonists, and new formulations have upgraded the management of breakthrough pain [37]; however, efforts to overcome the adverse effects of opioids have still met with limited success.…”

Section: Discussionmentioning

confidence: 99%

Effects of Ultramicronized N-Palmitoylethanolamine Supplementation on Tramadol and Oxycodone Analgesia and Tolerance Prevention

et al. 2022

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Chronic pain management requires increasing doses of opioids, the milestone of painkillers, which may result in the onset of tolerance with exacerbated side effects. Maintaining stable analgesia with low doses of opioids is thus imperative. N-palmitoylethanolamine (PEA) is an endogenous lipid compound endowed with pain-relieving as well as anti-inflammatory properties. The ultramicronized formulation of PEA was recently demonstrated to be able to modulate morphine’s effects, delaying tolerance and improving efficacy. To evaluate the possible application to other opioids, in this study, we analysed the capacity of ultramicronized PEA to regulate analgesia and tolerance induced by oxycodone and tramadol. Pre-emptive and continuative treatment with ultramicronized PEA (30 mg kg−1, daily, per os) delayed the onset of opioid tolerance and enhanced opioid analgesia when it was acutely administered in association with tramadol (20 mg kg−1, daily, subcutaneously) or oxycodone (0.5 mg kg−1, daily, subcutaneously). Moreover, PEA exerted antinociceptive effects on tolerant rats, suggesting the use of PEA together with opioids for stable, long-lasting analgesia. To that purpose, the oxycodone dose needed to be increased from 0.3 mg kg−1 (day 1) up to 1 mg kg−1 (day 31) in the oxycodone + vehicle group; the tramadol dose was progressively enhanced from 15 mg kg−1 to 50 mg kg−1 in 31 days in the tramadol + vehicle group. Acute oral co-treatment with PEA (120 mg kg−1) achieved the same analgesia without increasing the dose of both opioids. The behavioural effects of PEA on opioid chronic treatment paralleled a decrease in astrocyte activation in the dorsal horn of the spinal cord (a marker of the development of opioid tolerance) and with a modulation of mRNA expression of IL-6 and serpin-A3. In conclusion, pre- and co-administration of ultramicronized PEA delayed the development of tramadol tolerance, potentiating either oxycodone or tramadol analgesia and allowing a long-lasting analgesic effect with a low opioid dose regimen. The use of PEA is suggested for clinical purposes to support the opioid-based management of persistent pain.

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Evaluation of the effects of metformin administration on morphine tolerance in mice

Cited by 6 publications

References 25 publications

Identification of Morphine and Heroin-Treatment in Mice Using Metabonomics

Identification of Morphine and Heroin-Treatment in Mice Using Metabonomics

The Influence of Sildenafil–Metformin Combination on Hyperalgesia and Biochemical Markers in Diabetic Neuropathy in Mice

Effects of Ultramicronized N-Palmitoylethanolamine Supplementation on Tramadol and Oxycodone Analgesia and Tolerance Prevention

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